Is GSC p.Pro16Ser (c.46C>T) pathogenic?

GSC p.Pro16Ser (c.46C>T) is classified Uncertain significance in GSC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). AlphaMissense: likely benign (0.3192); Very rare (popmax 0.00185%, amr).

How common is GSC p.Pro16Ser (c.46C>T) in the general population?

GSC p.Pro16Ser (c.46C>T) is very rare (popmax 0.00185%, amr) (gnomAD).

What do computational predictors say about GSC p.Pro16Ser (c.46C>T)?

AlphaMissense predicts likely benign (score 0.3192) — an in-silico prediction, not a clinical call.

GSC p.Pro16Ser

c.46C>T · rs867113348 · VCV2493314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00185%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3192	likely benign
REVEL	0.538	indeterminate
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,521 bp · p 0.91 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00185% Admixed American · 1/53,930 alleles

Overall 6.42e-05% 1/1,557,282 alleles · very rare exomes 1/1,404,990 · genomes 0/152,292 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GSC
Protein: p.Pro16Ser
Coding: c.46C>T
MANE Select: NM_173849
dbSNP: rs867113348
Type: single nucleotide variant
Location: chr14:94769970 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.68 · 1 PDB

Full GSC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GSC p.Ala26Val Uncertain significance ★★ ⚠ same type
GSC p.Ala30Val Uncertain significance ★★ ⚠ same type
GSC p.Lys183Gln Uncertain significance ★★ ⚠ same type
GSC p.Tyr54Ser Uncertain significance ★★ ⚠ same type
GSC c.356-186C>T Benign ★★ same type
GSC p.Ala72Thr Benign ★★ same type
GSC p.Asn140= Benign/Likely benign ★★ same type
GSC p.Asp53= Benign/Likely benign ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gsc-p-pro16ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown